Combined argon laser photocoagulation and antivascular endothelial growth factor for management of macular polypoidal choroidal vasculopathy.

AIM: To evaluate the efficacy of combination therapy of argon laser photocoagulation and intravitreal antivascular endothelial growth factor (VEGF) injection in idiopathic polypoidal choroidal vasculopathy (PCV) involving macula.
MATERIALS AND METHODS: A retrospective interventional study involving 12 eyes of 11 patients diagnosed with PCV involving the macula on indocyanine green angiography (ICGA). Intravitreal anti-VEGF was given in eyes with significant subretinal/sub retinal pigment epithelium hemorrhage or exudation. ICGA-guided focal laser was done to extrafoveal leaking polyps. Mean change in best-corrected visual acuity (BCVA) and regression of polyp as seen on ICGA were evaluated at the final follow-up. STATISTICAL ANALYSIS: It was done using SPSS 17.0. - Mann-Whitney test.
RESULTS: 12 eyes of 11 patients underwent argon laser with intravitreal anti-VEGF injection. Ten patients were males and one female. Mean age was 65.75 ± 5.2 years. The mean number of injections given was 3.66 ± 1.5 (2-6) per eye. Mean number of laser sessions required was 1.33 ± 0.65 (1-3) per eye. BCVA improved in 25% (n = 3), remained stable in stable in 50% (n = 6) eyes, and decreased in 25% (n = 3) eyes. The regression of polypoidal lesions on ICGA was seen in 75% (n = 9) of eyes. Persistent subretinal fluid seen in 25% (n = 3) of eyes. The mean duration of follow-up was 15.41 ± 10.27 (3-36) months.
CONCLUSION: Combined argon laser photocoagulation with intravitreal anti-VEGF injection helps in decreasing exudation and results in stabilization of the disease with visual improvement in eyes with PCV involving macula.

Introduction

In 1982 Yannuzzi first described idiopathic polypoidal choroidal vasculopathy (PCV) as polypoidal, subretinal, vascular lesions associated with serous, and hemorrhagic detachments of retinal pigment epithelium (RPE) at the annual meeting of the American academy of ophthalmology.[1] The presence of orange – Red subretinal nodules with corresponding early-phase nodular hyperfluorescence from branching choroidal vasculature visualized using indocyanine green angiography (ICGA) is pathognomonic of PCV.[2] PCV is commonly diagnosed between the age of 50–65 years.[3] It can occur in any sex or race and is more commonly seen in nonwhite patients.[4] Polyps may be unilateral or bilateral, asymmetric and most commonly extrafoveal[5] and peripapillary.[4] It is a chronic disorder with variable natural course of the disease.[6] It may remain stable, resolve spontaneously or may cause repeated hemorrhage, and exudation resulting in fibrous scar.[7]

Various modalities of treatment described for symptomatic PCV include focal laser to extrafoveal polyps, photodynamic therapy (PDT) for subfoveal and juxtafoveal polyps, intravitreal anti-vascular endothelial growth factor (VEGF) therapy, or a combination therapy. Surgical treatment in the form of vitrectomy for nonresolving vitreous hemorrhage with or without intravitreal gas for the displacement of sub macular hemorrhage has also been described.

Focal argon laser of polyps has been the treatment of choice for extrafoveal PCV.[5] Anti-VEGF monotherapy has been known to effectively reduce macular edema and improve visual acuity, but the underlying polypoidal lesions may persist.[8] Koh et al. showed that anti-VEGF monotherapy was less effective than PDT in polyp closure.[9] In some cases even if subretinal fluid (SRF) and blood involve the fovea, ICGA may reveal a substantial proportion of polyps to be extrafoveal and amenable to focal argon laser photocoagulation once the surrounding SRF and hemorrhage subsides following intravitreal anti-VEGF injection. Hence, a combination therapy of thermal laser and anti-VEGF may be beneficial in a selected group of patients that present with macular involvement in PCV. Gemmy Cheung et al. showed a beneficial effect of argon laser treatment with selected use of anti-VEGF therapy in eyes with extrafoveal polyps, including eyes with fluid or blood involving the fovea at presentation.[10] Our study emphasizes the efficacy of combination therapy with argon laser photocoagulation and intravitreal injection of anti-VEGF for macula involving PCV.

Materials and Methods

Study design

Retrospective interventional study of 12 eyes of 11 patients that were diagnosed to have PCV by the presence of stippled hyperfluorescence on fundus fluorescein angiography (FFA), polypoidal choroidal nodules with or without branched vascular network of choroidal vessels on ICGA or dome-shaped steeply protruding RPE on optical coherence tomography (OCT) suggestive of polyps. Institute review board approval was obtained. All the tenants of the Declaration of Helsinki were followed.

Patients with symptomatic PCV having SRF/hemorrhage or serosanguineous pigment epithelial detachment (PED) involving the macula with extrafoveal location of leaking polyps seen on ICGA were included in the study. Patients with any contraindication to FFA or ICGA, or those with subfoveal polyps on ICGA were excluded from the analysis. Eyes with RPE tear and other maculopathies such as age-related macular degeneration (ARMD), diabetic macular edema, or myopia were also excluded from the study.

All patients underwent a complete ophthalmic examination which includes best-corrected visual acuity (BCVA) (measured on Snellen chart and converted to logarithm of the minimal angle of resolution [logMAR] units for analysis), dilated fundus examination, FFA, ICGA, and OCT. OCT was performed with the Cirrus OCT (Carl Zeiss Meditec, Dublin, California, USA) using the 512 × 128 volume cube setting. BCVA and OCT were performed at each follow-up visit. Repeat FFA or ICGA were performed if necessary as decided by the treating retinal specialist.

Thermal laser treatment

The focal thermal laser was done to the extrafoveal polyps as identified on ICGA. Treatment was performed with an argon green laser (532 mm) with a focal contact lens using the following parameters: 100 microns spot size with 100–150 ms duration and enough power to achieve a grayish-white burn to cover the active polypoidal lesions. Surrounding branching vascular network (BVN) was not treated. PED and subretinal hemorrhage were not included in the laser spot size. The laser was repeated at 1 month if resolution was believed to be incomplete at follow-up.

Antivascular endothelial growth factor therapy

Anti-VEGF therapy was used as an adjuvant to thermal laser due to the presence of significant submacular or sub-RPE hemorrhage or exudation at presentation, or because of the persistence of fluid after laser therapy. Intravitreal injection of bevacizumab (1.25 mg in 0.05 ml) or ranibizumab (0.5 mg in 0.05 ml) was given using a 30 guage needle under topical anesthesia and repeated after 4 weeks if persistent exudation was seen on OCT.

Outcome measures

Outcome measures were comparison of baseline and final BCVA, regression of polypoidal lesions on ICGA, resolution of SRF on OCT, number of laser sessions, and anti-VEGF injections required and any ocular/systemic adverse events. Statistical analysis was done using SPSS version 17.0 (SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc. Released 2008) and comparisons were done using Wilcoxon Mann-Whitney U-test.

Results

Twelve eyes of eleven patients were diagnosed to have symptomatic macular PCV on ICGA and OCT and underwent argon laser photocoagulation with intravitreal anti-VEGF injection. Ten patients were males and one female. Table 1 shows the clinical characteristics of the patients. The mean age at presentation was 65.75 years (standard deviation of 5.2 years). 45.5% (n = 5) had unilateral PCV and 54.5% (n = 6) had bilateral PCV. Among patients having bilateral disease, 9.09% (n = 1) had active polyps, 18.18% (n = 2) had symptomatic polyps, and 27.27% (n = 3) had macular scar in the fellow eye. 66.55% (n = 8) of eyes presented with hemorrhagic PCV (hemorrhagic PED and subretinal hemorrhage) and 33.33% (n = 4) of eyes presented with exudative PCV (serous PED with neurosensory retinal detachment). 25% (n = 3) of eyes received multiple sessions of thermal laser treatment. All the eyes received multiple anti-VEGF injections. Ten eyes had received bevacizumab, and two eyes had received ranibizumab intravitreal injection. In seven eyes (58.33%), anti-VEGF injection was given 3–4 weeks before laser treatment. These eyes had a large PED and/or massive hemorrhage at macula at presentation, obscuring any visible polyps on ICGA. The mean number of laser sittings received was 1.33 ± 0.65 (1–3) per eye, and the mean number of anti-VEGF injections received was 3.66 ± 1.5 (2–6) per eye.

Table 1

Combined argon laser photocoagulation and antivascular endothelial growth factor for management of macular polypoidal choroidal vasculopathy: Clinical characteristics

BCVA improved in 25% (n = 3) eyes from a mean baseline value of 1.03 ± 0.75 logMAR to 0.73 ± 0.55 logMAR, stable in 50% (n = 6) eyes with mean value of 0.74 + 0.71 logMAR and decreased in 25% (n = 3) eyes from mean baseline value of 0.43 ± 0.51 logMAR to 1.36 ± 0.75 logMAR at the final follow-up. The mean BCVA of patients with single session laser was 0.75 ± 0.6 logMAR at baseline and 0.742 ± 0.635 logMAR at final follow-up. The mean BCVA of patients with multiple session lasers was 0.69 ± 0.95 logMAR at baseline, and 1.36 ± 0.74 logMAR at final follow-up. BCVA was not statistically significant between these two groups with P = 0.729 and 0.209 at baseline and at final follow-up, respectively.

The regression of polypoidal lesions on ICGA was seen in 75% (n = 9) of eyes. Persistent SRF seen in 25% (n = 3) of eyes. Of the three eyes which showed deterioration of vision, one eye had a large area of hemorrhage at presentation and at subsequent follow-up was seen to have multiple polyps with massive exudation not amenable to further focal laser treatment. The second eye showed development of subfoveal choroidal neovascular membranes which caused a decrease in BCVA. The third eye developed subfoveal leaking polyps which could not be treated with laser and patient could not afford PDT. The patient was given multiple injections of bevacizumab following which SRF decreased but polyps were seen to persist subfoveal, and the BCVA dropped from 6/6 to 6/18 at the last follow-up. No systemic or ocular adverse were events noted during the follow-up. The mean duration of follow-up was 15.41 ± 10.27 months.

Discussion

PCV needs to be distinguished from the other disorders such as ARMD with CNV as the nature of the disease, and the treatment protocol differs from each other. ICGA helps to distinguish between these diseases. The mean age of presentation in our study was 65.75 years which was comparable with the other studies in Asia.[1112] The studies done in Asia showed PCV often presents as a unilateral[1112] and as macular disease.[713]

Matsuoka et al. showed upregulation of VEGF in PCV which explains the efficacy of anti-VEGF in the treatment of PCV.[14] Cho et al. showed that 77.7% (n = 21) eyes had stable or improved visual acuity with anti-VEGF monotherapy in eyes with submacular hemorrhage associated with PCV.[15] Although monotherapy with anti-VEGF decreases submacular hemorrhage and SRF, regression of polypoidal lesions is limited. Kokame et al. showed bevacizumab monotherapy resulted in 33% of the resolution of PCV lesions with persisting branching choroidal vessels.[16] Few more studies have shown the ineffectiveness of bevacizumab monotherapy in the regression of polyps.[1718] Hence, it is advisable to use anti-VEGF as an adjunctive to the thermal laser photocoagulation or PDT. PDT combined with anti-VEGF reduces side effects of PDT, like massive subretinal or vitreous hemorrhage.[9] PDT is expensive and has limited accessibility, not all patients can afford it, especially in the third world countries where its cost is not reimbursed.

Laser photocoagulation also helps in closure of polypoidal lesions but cannot be used in subfoveal polyps. A careful analysis of ICGA helps in identifying a laserable polyp even in some cases of macular PCV. The presence of dense subretinal hemorrhage or sub-RPE hemorrhage may not allow visualization of polyps on ICGA or increased retinal thickness may not allow laser to penetrate up to the inner choroidal layer. Modification of therapy by giving anti-VEGF 3–4 weeks before laser treatment can increase the chances of detecting the polyps by imaging techniques and treat the same by definitive treatment like PDT or focal laser giving good results in selected cases. Anti-VEGF also decreases retinal thickness so that laser can be effective. Figure 1 shows the fundus photograph with ICGA and OCT findings before and after anti-VEGF and then followed by thermal laser photocoagulation of the polyps in two patients. The effect of doing laser photocoagulation for both polyps and BVN has been studied with varied results. Gomez-Ulla et al. have shown that applying laser to both polyps and the BVN resulted in poor final visual acuity.[19] On the other side Yuzawa et al. reported that only 10% of eyes worsened if both the polyp and network underwent laser treatment, compared with 54% of eyes that worsened after laser treatment to polyps only. However, applying laser to the entire BVN often is not possible because of the large area involved, often indistinct border of the BVN, and concomitant hemorrhage.[20] No case of massive subretinal hemorrhage or breakthrough vitreous hemorrhage was seen.

Figure 1

(a) Hemorrhagic pigment epithelial detachment seen inferonasal to fovea with multiple polyps. 1: Fundus photo, 2: Fundus fluorescein angiography, 3: Indocyanine green angiography, 4 and 5: Optical coherence tomography before anti-vascular endothelial growth factor + laser and after, respectively, (b) macular polypoidal choroidal vasculopathy with extrafoveal polyp treated with laser. 1: Fundus photo, 2: Fundus fluorescein angiography, 3: Indocyanine green angiography showing the polyps in papillomacular bundle, 4 and 5: Optical coherence tomography before and after laser, respectively

This could also be because anti-VEGF was used first in some cases with large PED to reduce exudation before attempting laser.

Our study showed 75% of eyes had stable or improved vision after the treatment with both laser and anti-VEGF. Rishi et al. have reported a case of PCV treated with laser and anti-VEGF with improved visual acuity at 6 weeks.[21] The previous study by Gemmy Cheung et al. has reported stable or improved visual acuity at 12 months follow-up in 90.3% of eyes which received adjunctive anti-VEGF therapy along with thermal laser therapy.[10] Combined laser and anti-VEGF therapy help in better stabilization or improvement of BCVA. Our study is limited by its retrospective nature, small number of cases, and absence of randomized comparative data.

Conclusion

Our series has shown that use of combined argon laser photocoagulation and anti-VEGF for the management of PCV involving macula is effective in achieving stable or improved visual outcome in 75% of eyes. Treatment protocols may need to be individualized. Meticulous analysis of ICGA allows thermal laser even in patients with macular PCV. We recommend combined thermal laser and anti-VEGF in the treatment of selective cases of macular PCV.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.